ARCH
Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques
Year of Publication: 2014
Authors: Pierre Amarenco, Stephen Davis, Elizabeth F. Jones, ..., for the ARCH Investigators
Journal: Stroke
Citation: Stroke. 2014;45:1248-1257.
Link: https://doi.org/10.1161/CIRCULATIONAHA.113.006207
PDF: https://www.ahajournals.org/doi/pdf/10.1...EAHA.113.004251
PDF: Clinical Question
In patients with ischemic stroke/TIA/peripheral embolism attributed to thoracic aortic plaque ≥4mm with no other embolic source, is aspirin + clopidogrel superior to dose-adjusted warfarin (INR 2-3)?
Bottom Line
Aspirin + clopidogrel did not significantly reduce the composite primary endpoint vs warfarin (7.6% vs 11.3%; adjusted HR 0.76; 95% CI 0.36-1.61; P=0.5) after median 3.4 years. Vascular death was significantly lower with DAPT (0% vs 3.4%; P=0.013), though trial was severely underpowered (349 of planned 744+ patients) and results are hypothesis-generating only.
Major Points
- Primary endpoint not different: 7.6% (DAPT) vs 11.3% (warfarin); adjusted HR 0.76 (95% CI 0.36-1.61; P=0.5).
- Vascular death: 0% (DAPT) vs 3.4% (warfarin); log-rank P=0.013 — only significant endpoint, but likely chance given underpowering.
- Severely underpowered: only 349 of planned 744+ patients; only 33 of required ≥70 primary events. Stopped for exhausted funding after 8+ years.
- Observed event rate far lower than expected: 3.5%/year vs expected 12%/year — modern secondary prevention dramatically reduced risk.
- On-treatment LDL reduced ~40 mg/dL, SBP ~130 mmHg in both arms — aggressive background therapy.
- Major hemorrhage similar: 2.3% (DAPT) vs 3.4% (warfarin); P=0.17.
- Warfarin TTR 67% (INR 2-3), 76% (INR 1.8-3.2). Trend: DAPT better at low TTR, warfarin better at high TTR.
- Aortic arch plaque ≥4mm diagnosed by TEE. 65-66% qualifying event was ischemic stroke, 31-33% TIA.
- High cardiovascular risk: 66% smokers, 73% hypertension, 67% hyperlipidemia.
- Authors suggest DAPT may be preferred given simpler monitoring, no INR requirement. Future trials should compare antiplatelet vs DOACs.
Design
Study Type: Prospective randomized controlled superiority trial (PROBE design)
Randomization: 1
Blinding: Open-label treatment; blinded endpoint evaluation. 1:1 computer-based randomization.
Enrollment Period: February 1, 2002 to May 6, 2010 (~8 years)
Follow-up Duration: Median 3.4 years (range 1-8 years)
Centers: 40
Countries: France, Australia, Switzerland
Sample Size: 349
Analysis: Intention-to-treat. Cox proportional hazards. Triangular sequential design (planned interim at ≥70 events — never reached).
Inclusion Criteria
- Age >18 years.
- Nondisabling ischemic stroke, TIA, or peripheral embolism (mRS <4).
- Atherosclerotic plaque ≥4mm in thoracic aorta on TEE.
- No other recognized embolic source.
- Embolic event downstream from the observed plaque.
- Willing for 3-year follow-up.
Exclusion Criteria
- Women of childbearing potential.
- Overt cardiac source of embolism (mitral stenosis, endocarditis, AF).
- Extracranial atherosclerotic stenosis ≥70%.
- Intracranial atherosclerotic stenosis ≥70%.
- Scheduled carotid revascularization.
- Cerebral artery dissection.
- Other uncommon stroke cause.
- Absolute indication for oral anticoagulant.
- Contraindication to aspirin, clopidogrel, or TEE.
Baseline Characteristics
| Characteristic | Aspirin + Clopidogrel (N=172) | Warfarin (N=177) |
|---|---|---|
| Age (mean±SD) | 69.2±9.2 | 69.7±9.0 |
| Male | 119 (69.2%) | 131 (74.0%) |
| Hypertension | 127 (74.3%) | 129 (74.5%) |
| Hyperlipidemia | 119 (69.6%) | 113 (66.1%) |
| Diabetes type 2 | 35 (20.8%) | 32 (18.9%) |
| Current smoker | 112 (65.5%) | 118 (68.2%) |
| Prior ischemic stroke | 47 (27.3%) | 51 (28.8%) |
| Prior MI | 13 (8.0%) | 28 (17.3%) |
| Qualifying — Ischemic stroke | 113 (65.7%) | 122 (68.9%) |
| Qualifying — TIA | 58 (33.7%) | 55 (31.1%) |
| SBP (mean±SD) | 135.5±15.9 mmHg | 135.2±18.9 mmHg |
| LDL-C (mean±SD) | 122±40 mg/dL | 125±50 mg/dL |
Arms
| Field | Aspirin + Clopidogrel | Control |
|---|---|---|
| Intervention | Aspirin 75-150 mg/day (per local rules) + clopidogrel 75 mg/day. | Warfarin with target INR 2.5 (range 2-3). TTR 67% (INR 2-3). 21% permanently discontinued. |
| Duration | Median 3.4 years. 15% permanently discontinued. | Median 3.4 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite: ischemic stroke, MI, peripheral embolism, vascular death, or intracranial hemorrhage | Primary | 20/177 (11.3%); 3.49/100 py | 13/172 (7.6%); 2.17/100 py | 3.74% | 0.5 |
| Ischemic stroke | Secondary | 9 (5.1%) | 11 (6.4%) | Adjusted HR 1.82 | 0.2 |
| Vascular death | Secondary | 6 (3.4%) | 0 (0%) | — | 0.013 (log-rank) |
| Total death | Secondary | 15 (8.4%) | 8 (4.7%) | Adjusted HR 0.58 | 0.3 |
| Net benefit (primary + major hemorrhage) | Secondary | 24 (13.6%) | 17 (9.9%) | Adjusted HR 0.79 | 0.5 |
| Major hemorrhage | Adverse | 6 (3.4%) | 4 (2.3%) | 0.17 | |
| Intracranial hemorrhage | Adverse | 1 (0.6%) — fatal | 2 (1.2%) — both nonfatal |
Subgroup Analysis
TTR tertile analysis: DAPT trended better at low TTR (<64%: HR 0.46); warfarin better at high TTR (>77%: HR 2.06). No significant heterogeneity (P=0.4).
Criticisms
- Severely underpowered: 349/744+ patients, 33/70+ events needed. Stopped for funding exhaustion.
- Open-label treatment (PROBE design).
- Event rate 3.5%/year vs expected 12%/year — designed on outdated 1996 estimates.
- Baseline imbalance in prior MI (8% vs 17.3%).
- No aspirin monotherapy arm.
- 8+ year enrollment — guidelines evolved significantly.
- No NOAC comparator (designed pre-NOAC era).
- Limited geography (France, Australia, Switzerland).
Funding
French PHRC (AOM 97211/P991205); Australian NHMRC; SOS-Attaque Cerebrale. Sanofi and Bristol-Myers Squibb provided drugs (no role in trial).
Based on: ARCH (Stroke, 2014)
Authors: Pierre Amarenco, Stephen Davis, Elizabeth F. Jones, ..., for the ARCH Investigators
Citation: Stroke. 2014;45:1248-1257.
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